Whole exome sequencing of extreme age-related macular degeneration phenotypes

Rebecca J. Sardell, Jessica N Cooke Bailey, Monique D. Courtenay, Patrice Whitehead, Reneé A. Laux, Larry D. Adams, Jorge Fortun, Milam A. Brantley, Jaclyn Kovach, Stephen Schwartz, Anita Agarwal, William K Scott, Jonathan L. Haines, Margaret A Pericak-Vance

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose: Demographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes. Methods: A genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex. Results: No variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: An intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls. Conclusions: Identified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.

Original languageEnglish (US)
Pages (from-to)1062-1076
Number of pages15
JournalMolecular Vision
Volume22
StatePublished - Aug 29 2016

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Exome
Macular Degeneration
Phenotype
Gene Frequency
Genes
Pyridoxal
Choroidal Neovascularization
Pyridoxine
Photoreceptor Cells
Vitamin B 6
Genetic Loci
Meta-Analysis
Cell Death
Phosphotransferases
Nucleotides

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Sardell, R. J., Bailey, J. N. C., Courtenay, M. D., Whitehead, P., Laux, R. A., Adams, L. D., ... Pericak-Vance, M. A. (2016). Whole exome sequencing of extreme age-related macular degeneration phenotypes. Molecular Vision, 22, 1062-1076.

Whole exome sequencing of extreme age-related macular degeneration phenotypes. / Sardell, Rebecca J.; Bailey, Jessica N Cooke; Courtenay, Monique D.; Whitehead, Patrice; Laux, Reneé A.; Adams, Larry D.; Fortun, Jorge; Brantley, Milam A.; Kovach, Jaclyn; Schwartz, Stephen; Agarwal, Anita; Scott, William K; Haines, Jonathan L.; Pericak-Vance, Margaret A.

In: Molecular Vision, Vol. 22, 29.08.2016, p. 1062-1076.

Research output: Contribution to journalArticle

Sardell, RJ, Bailey, JNC, Courtenay, MD, Whitehead, P, Laux, RA, Adams, LD, Fortun, J, Brantley, MA, Kovach, J, Schwartz, S, Agarwal, A, Scott, WK, Haines, JL & Pericak-Vance, MA 2016, 'Whole exome sequencing of extreme age-related macular degeneration phenotypes', Molecular Vision, vol. 22, pp. 1062-1076.
Sardell RJ, Bailey JNC, Courtenay MD, Whitehead P, Laux RA, Adams LD et al. Whole exome sequencing of extreme age-related macular degeneration phenotypes. Molecular Vision. 2016 Aug 29;22:1062-1076.
Sardell, Rebecca J. ; Bailey, Jessica N Cooke ; Courtenay, Monique D. ; Whitehead, Patrice ; Laux, Reneé A. ; Adams, Larry D. ; Fortun, Jorge ; Brantley, Milam A. ; Kovach, Jaclyn ; Schwartz, Stephen ; Agarwal, Anita ; Scott, William K ; Haines, Jonathan L. ; Pericak-Vance, Margaret A. / Whole exome sequencing of extreme age-related macular degeneration phenotypes. In: Molecular Vision. 2016 ; Vol. 22. pp. 1062-1076.
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abstract = "Purpose: Demographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes. Methods: A genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1{\%} minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1{\%} MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex. Results: No variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: An intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls. Conclusions: Identified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.",
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AU - Bailey, Jessica N Cooke

AU - Courtenay, Monique D.

AU - Whitehead, Patrice

AU - Laux, Reneé A.

AU - Adams, Larry D.

AU - Fortun, Jorge

AU - Brantley, Milam A.

AU - Kovach, Jaclyn

AU - Schwartz, Stephen

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AU - Pericak-Vance, Margaret A

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N2 - Purpose: Demographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes. Methods: A genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex. Results: No variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: An intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls. Conclusions: Identified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.

AB - Purpose: Demographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes. Methods: A genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex. Results: No variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: An intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls. Conclusions: Identified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.

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